Abstract |
A wide range of anti- cancer drugs are substrates of the ATP-binding cassette transporter ABCG2/CD338/BCRP/MXR, which is thought to play an important role in multi-drug resistance (MDR) and protection of cancer stem cells (CSC) against chemotherapeutics and photodynamic therapy ( PDT). Hence, it is of importance to develop drugs that are not substrates of ABCG2. The aim of this study was to elucidate if photosensitizers utilized for the endo-lysosomal release drug delivery method photochemical internalization (PCI) are substrates for ABCG2. The breast carcinoma cell line MA11, with a Hoechst 33342 side population of >50% was used as an ABCG2high model. The photosensitizer Pheophorbide A (PhA) and Hoechst 33342 were used as positive control substrates of ABCG2. ABCG2-inhibition by fumitremorgin C ( FTC) did neither induce an increased accumulation of three different PCI- photosensitizers (di-sulfonated meso- tetraphenylporphine ( TPPS(2a)), di-sulfonated meso-tetraphenylchlorin (TPCS(2a)) and di-sulfonated aluminium phtalocyanine (AlPcS(2a))) nor enhanced the photosensitization (P=0.65 for TPCS(2a)- PDT) of these PCI-based photosensitizers in the MA11 cells. The same results were also obtained with TPPS(2a) in the malignant glioma cell line U87 having a SP of ~0.1%. In contrast, both uptake and PDT-induced cytotoxicity was strongly enhanced for PhA when combined with FTC (P<0.001)). Specific and efficient light-controlled killing of EGFR+/ABCG2+ MA11 cells was obtained by PCI of the targeting toxin EGF- saporin. The novel data obtained in this study demonstrates that strongly amphiphilic photosensitizers used for PCI-based drug delivery are not substrates of ABCG2. This important findings warrant further development of the PCI technology as a strategy for efficient and site-specific eradication of MDR cells and CSC.
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Authors | Pål Kristian Selbo, Anette Weyergang, Marius Strømbo Eng, Monica Bostad, Gunhild M Mælandsmo, Anders Høgset, Kristian Berg |
Journal | Journal of controlled release : official journal of the Controlled Release Society
(J Control Release)
Vol. 159
Issue 2
Pg. 197-203
(Apr 30 2012)
ISSN: 1873-4995 [Electronic] Netherlands |
PMID | 22349185
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2012 Elsevier B.V. All rights reserved. |
Chemical References |
- ABCG2 protein, human
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
- Drug Carriers
- Neoplasm Proteins
- Photosensitizing Agents
- Porphyrins
- Surface-Active Agents
- di(4-sulfonatophenyl)diphenylporphine
- meso-tetraphenyl chlorin disulphonate
- EGFR protein, human
- ErbB Receptors
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Topics |
- ATP Binding Cassette Transporter, Subfamily G, Member 2
- ATP-Binding Cassette Transporters
(biosynthesis, metabolism)
- Cell Line, Tumor
- Cell Survival
(drug effects, radiation effects)
- Drug Carriers
(chemistry, pharmacology)
- Drug Resistance, Multiple
(drug effects, radiation effects)
- Drug Resistance, Neoplasm
(drug effects, radiation effects)
- Endocytosis
(drug effects, radiation effects)
- ErbB Receptors
(metabolism)
- Flow Cytometry
- Humans
- Light
- Microscopy, Fluorescence
- Molecular Structure
- Neoplasm Proteins
(biosynthesis, metabolism)
- Photosensitizing Agents
(chemistry, pharmacology)
- Porphyrins
(chemistry, pharmacology)
- Substrate Specificity
- Surface-Active Agents
(chemistry, pharmacology)
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